OC 8405 Identification of an MTB-specific soluble host signature for risk of development of active TB in HIV-positive MTB-exposed contacts. (24th April 2019)

• Record Type: Journal Article
• Authors: Mendy, Joseph; Chegou, Novel N; Mayanja-Kizza, Harriet; Stanley, Kim; Thiel, Bonnie; Ottenhoff, Tom; Kaufmann, Stefan; Boom, Henry; Walzl, Gerhard; Sutherland, Jayne
• Is Part Of: BMJ global health. Volume 4(2019)Supplement 3
• Page Start: A5
• Page End: A5
• Publication Date: 2019-04-24
• Subjects: World health -- Periodicals; 362.105
• DOI: 10.1136/bmjgh-2019-EDC.10
• Languages: English
• ISSNs: 2059-7908

Abstract

Abstract : Background: With 2 billion people infected with Mycobacterium tuberculosis (Mtb) worldwide, identification of those most at-risk of progressing to active disease would provide a targeted, cost-effective approach for preventative therapy strategies. The GC6–74 project recruited Mtb-exposed HIV-positive (HIV+) contacts from 5 African countries with the aim of identifying molecular and protein signatures for identification of 'at-risk' subjects by comparing those who progressed to active disease (progressors) to those who remained asymptomatic (controls). Methods: For this arm of the project, we analysed longitudinal samples from 12 HIV +progressors and 28 HIV +matched controls from Uganda (Makerere University, MAK) and South Africa (Stellenbosch University, SUN). Diluted whole blood was stimulated for 7 days with 7 Mtb-specific antigens plus controls. Supernatant was collected and a 38-plex multiplex assay performed following identification of confirmed progressors and controls. Results: The median time to progression to active disease was 510 days for SUN and 425 days for MAK participants. Baseline CD4 counts were 163 cells/µl for progressors and 154 cells/µl for controls. Baseline responses showed significantly lower IL-4 production in progressors following ESAT-6/CFP-10 (EC) stimulation (p=0.0309) and significantly higher macrophage-derived chemokine (MDC) following both Rv3019 and TB10.4 stimulation. For the time-point closest to progression, IL-10 production following EC stimulation and IFN-γ production following Rv3019 stimulation were significantly higher in progressors than controls (p=0.0024 and p=0.0028 respectively). A combination of 12 analytes following EC and TB10.4 stimulation gave 84.4% and 91.1% correct classification respectively. Conclusion: We have defined a soluble signature for detecting likely progression to active TB in HIV +subjects 1 year prior to progression. Following validation in other cohorts, this could be exploited for development of a field-friendly test for targeted interventional therapy.